Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response

保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态

• 批准号: 10231081
• 负责人: James J Kobie
• 金额: $ 75.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231081
• 关键词: Adjuvant; Adult; Animals; Antibodies; Antibody Repertoire; Antibody Response; Antibody Specificity; Antiviral Agents; B-Cell Antigen Receptor; B-Lymphocytes; Blood Circulation; Bone Marrow; Cavia; Cell Lineage; Cells; Characteristics; Clone Cells; Dependence; Development; Epitopes; Evolution; Frequencies; Future; Genetic; Glycoproteins; Hemagglutinin; Human; Immune response; Immunity; Immunization; Immunoglobulin G; In Vitro; Infection; Influenza; Influenza B Virus; Influenza Hemagglutinin; Intramuscular; Lung Inflammation; MF59; Mediating; Modality; Monoclonal Antibodies; Mus; Mutation; Neuraminidase; Plasma Cells; Prevention; Process; Production; Property; Proteins; Research; Resolution; Seasons; Serum; Severity of illness; Site; Source; Specificity; Surface; Testing; Therapeutic; Translating; Vaccination; Vaccines; Viral; Viral Physiology; Virion; Virus; Virus Shedding; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; complement pathway; deep sequencing; flu transmission; human monoclonal antibodies; immunogenic; in vivo; influenza infection; influenza virus vaccine; insight; novel vaccines; pandemic influenza; peripheral blood; prevent; resistant strain; response; transcriptomics; transmission process; universal vaccine; vaccine development

PROJECT SUMMARY The human immune response against influenza is dominated by the production of hemagglutinin (HA)-specific antibodies (Abs). The yearly mutation rate in influenza HA proteins is 1-2% leading to development of new viral strains that are resistant to previous immunity. The other most predominant glycoprotein on the virion surface is neuraminidase (NA). Although immunogenic, predominance of human NA-specific Abs is much lower than HA, probably because NA expression is only one fourth the amount of HA on the virion surface. The yearly rate of mutation of NA is about half that of HA while part of the enzymatic site remains conserved across type A (IAV) and B (IBV) influenza viruses, making NA a potentially effective target for universal vaccine and therapeutic human monoclonal Ab (hmAb) development. Antibody responses targeting NA have demonstrated protective and therapeutic activity against influenza infection in animals, and in humans NA-inhibiting serum Abs have been correlated with effective protection, reduced disease severity, and duration of viral shedding, independent of or more strongly than HA-specific Ab responses, substantiating NA as a valuable target for the prevention and treatment of influenza in humans. Although seasonal human inactivated influenza vaccines (IIV) contain NA, the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Our research has demonstrated that IIV in humans does induce both IAV and IBV NA- specific B cells, and that the Ab clonal lineages they encode for include those that have broad and potent ability to protect and treat influenza infection. Further, we have demonstrated that these protective NA-specific B cell clonal lineages are present in long-lived bone marrow plasma cells in humans following IIV and are the likely source for their sustained presence in circulation. We posit that NA-mediated universal humoral protection, like HA, is dependent on B cell receptor/Ab specificity, however, to a greater extent than HA is also highly dependent on the precise Fc/IgG subclass composition of the NA-specific Ab repertoire. Our central hypothesis is that human IIV induces NA-specific B cell responses with broad protective potential, however, those with both the proper specificity and anti-viral activity to confer universal protection are subdominant and sporadically induced, hence at insufficient abundance to confer optimal protection. Through precisely defining the dynamics of those protective human NA-specific B cell clonal lineages, including their induction, frequency, persistence, precise specificity, and mechanisms of action, we expect to obtain insight on how to optimally stimulate them for future human universal vaccine strategies. To that end, we propose 1) define the evolution of human NA-specific B cell clonal lineages in response to seasonal IIV 2) assess the ability of IIV-induced human NA B cell lineages to inhibit infection and transmission and 3) evaluate the Fc-dependence of NA-specific hmAb protection. The process for the development of protective human NA-specific B cell clonal lineages will be defined and strategies to translate this to universal human vaccine-mediated protection from influenza infection identified.

项目摘要 人类对流感的免疫反应主要由血凝素（HA）特异性产生 抗体（ABS）。流感HA蛋白的年度突变率为1-2％，导致新病毒的发展 对先前免疫力有抗性的菌株。病毒体表面上的另一个主要主要糖蛋白是 神经氨酸酶（NA）。尽管免疫原性，但人Na特异性ABS的占主导地位远低于HA，但 可能是因为Na表达仅是病毒体表面上HA量的四分之一。年度 Na的突变约为HA的一半，而酶位的一部分在A型（IAV）中仍然保守 和B（IBV）流感病毒，使NA成为通用疫苗和治疗的潜在有效靶标 人类单克隆AB（HMAB）开发。靶向Na的抗体反应已显示出保护性 和针对动物中流感感染的治疗活性以及人类抑制血清ABS的治疗活性已是 与有效的保护，疾病严重程度降低和病毒脱落的持续时间相关，与OR无关 比HA特定的AB响应更强烈，证明NA是预防的宝贵目标和 治疗人类流感。尽管季节性人类灭活流感疫苗（IIV）含有NA，但 疫苗接种引起的保护性人NA特异性体液反应的作用的程度和机制 解决方案很差。我们的研究表明，人类IIV确实会诱导IAV和IBV Na- 特定的B细胞，AB克隆谱系编码的谱系包括具有广泛和有效能力的谱系 保护和治疗流感感染。此外，我们已经证明了这些保护性NA特异性B细胞 在IIV之后，人类长寿命的骨髓细胞中存在克隆谱系，并且可能是 他们在循环中持续存在的来源。我们认为NA介导的普遍的体液保护，例如 HA，取决于B细胞受体/AB的特异性，而HA的程度也比HA高度依赖 在NA特异性AB曲目的精确FC/IgG亚类组成上。我们的中心假设是 人类IIV诱导具有广泛保护潜力的Na特异性B细胞反应，但是 适当的特异性和抗病毒活性以赋予普遍保护是亚辅助和偶发诱导的， 因此，以不足以提供最佳保护。通过精确定义那些动态 保护性人Na特异性B细胞克隆谱系，包括其诱导，频率，持久性，精确 我们希望特异性和作用机理能够获得有关如何最佳刺激它们未来的见解 人类通用疫苗策略。为此，我们提出1）定义人Na特异性B细胞的演变 克隆谱系响应季节性IIV 2）评估IIV诱导的人Na B细胞谱系的能力 抑制感染和传播以及3）评估Na特异性HMAB保护的FC依赖性。这 将定义开发保护性人Na特异性B细胞克隆谱系的过程和策略 将其转化为普遍的人疫苗介导的保护免受鉴定的流感感染的保护。